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Molecular Research on Rett Syndrome and Related Disorders 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 9652

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Special Issue Editor

Dr. Maria J. Diogenes

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Guest Editor

1. Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
2. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Interests: Rett syndrome; epilepsy; BDNF; neurotrophins; adenosine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rett syndrome (RTT) is a serious lifelong neurodevelopmental disorder mainly caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2; OMI#300005). However, many atypical cases of Rett syndrome have been associated with mutations in other genes, such as the X-linked cyclin-dependent kinase-like 5 (CDKL5; OMIM #300203) or the Forkhead box G1 (FOXG1; OMIM #164874). In addition, in recent years, more genes have been related to the RTT-like phenotype, and some of these genes have also been identified as causative for atypical RTT or RTT-like phenotype in patients.

To date, there has been a lack of therapeutic strategies to help these patients, and it is crucial to shed light on the many unknown aspects of these disorders. Therefore, this Special Issue provides a forum for the publication of top-quality research papers on molecular and cellular mechanisms underlying Rett syndrome and related disorders, the neural systems and underpinning behavioral-associated features and findings relevant to the development of new therapies.

Dr. Maria J. Diogenes
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

Rett syndrome
atypical Rett
epileptic encephalopathies
neurodelopmental disorders
MECP2
FOXG1
CDKL5

Published Papers (4 papers)

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Research

18 pages, 12528 KiB

Open AccessArticle

A Comprehensive and Integrative Approach to MeCP2 Disease Transcriptomics

by Alexander J. Trostle, Lucian Li, Seon-Young Kim, Jiasheng Wang, Rami Al-Ouran, Hari Krishna Yalamanchili, Zhandong Liu and Ying-Wooi Wan

Int. J. Mol. Sci. 2023, 24(6), 5122; https://doi.org/10.3390/ijms24065122 - 7 Mar 2023

Cited by 2 | Viewed by 1425

Abstract

Mutations in MeCP2 result in a crippling neurological disease, but we lack a lucid picture of MeCP2′s molecular role. Individual transcriptomic studies yield inconsistent differentially expressed genes. To overcome these issues, we demonstrate a methodology to analyze all modern public data. We obtained relevant raw public transcriptomic data from GEO and ENA, then homogeneously processed it (QC, alignment to reference, differential expression analysis). We present a web portal to interactively access the mouse data, and we discovered a commonly perturbed core set of genes that transcends the limitations of any individual study. We then found functionally distinct, consistently up- and downregulated subsets within these genes and some bias to their location. We present this common core of genes as well as focused cores for up, down, cell fraction models, and some tissues. We observed enrichment for this mouse core in other species MeCP2 models and observed overlap with ASD models. By integrating and examining transcriptomic data at scale, we have uncovered the true picture of this dysregulation. The vast scale of these data enables us to analyze signal-to-noise, evaluate a molecular signature in an unbiased manner, and demonstrate a framework for future disease focused informatics work. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders 2.0)

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19 pages, 2456 KiB

Open AccessArticle

Global Impairment of Immediate-Early Genes Expression in Rett Syndrome Models and Patients Linked to Myelination Defects

by Paolo Petazzi, Olga Caridad Jorge-Torres, Antonio Gomez, Iolanda Scognamiglio, Jordi Serra-Musach, Angelika Merkel, Daniela Grases, Clara Xiol, Mar O’Callaghan, Judith Armstrong, Manel Esteller and Sonia Guil

Int. J. Mol. Sci. 2023, 24(2), 1453; https://doi.org/10.3390/ijms24021453 - 11 Jan 2023

Cited by 4 | Viewed by 2486

Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disease caused almost exclusively by mutations to the MeCP2 gene. This disease may be regarded as a synaptopathy, with impairments affecting synaptic plasticity, inhibitory and excitatory transmission and network excitability. The complete understanding of the mechanisms behind how the transcription factor MeCP2 so profoundly affects the mammalian brain are yet to be determined. What is known, is that MeCP2 involvement in activity-dependent expression programs is a critical link between this protein and proper neuronal activity, which allows the correct maturation of connections in the brain. By using RNA-sequencing analysis, we found several immediate-early genes (IEGs, key mediators of activity-dependent responses) directly bound by MeCP2 at the chromatin level and upregulated in the hippocampus and prefrontal cortex of the Mecp2-KO mouse. Quantification of the IEGs response to stimulus both in vivo and in vitro detected an aberrant expression pattern in MeCP2-deficient neurons. Furthermore, altered IEGs levels were found in RTT patient’s peripheral blood and brain regions of post-mortem samples, correlating with impaired expression of downstream myelination-related genes. Altogether, these data indicate that proper IEGs expression is crucial for correct synaptic development and that MeCP2 has a key role in the regulation of IEGs. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders 2.0)

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20 pages, 4002 KiB

Open AccessArticle

Meta-Analysis Identifies BDNF and Novel Common Genes Differently Altered in Cross-Species Models of Rett Syndrome

by Florencia Haase, Rachna Singh, Brian Gloss, Patrick Tam and Wendy Gold

Int. J. Mol. Sci. 2022, 23(19), 11125; https://doi.org/10.3390/ijms231911125 - 22 Sep 2022

Cited by 5 | Viewed by 2648

Abstract

Rett syndrome (RTT) is a rare disorder and one of the most abundant causes of intellectual disabilities in females. Single mutations in the gene coding for methyl-CpG-binding protein 2 (MeCP2) are responsible for the disorder. MeCP2 regulates gene expression as a transcriptional regulator as well as through epigenetic imprinting and chromatin condensation. Consequently, numerous biological pathways on multiple levels are influenced. However, the exact molecular pathways from genotype to phenotype are currently not fully elucidated. Treatment of RTT is purely symptomatic as no curative options for RTT have yet to reach the clinic. The paucity of this is mainly due to an incomplete understanding of the underlying pathophysiology of the disorder with no clinically useful common disease drivers, biomarkers, or therapeutic targets being identified. With the premise of identifying universal and robust disease drivers and therapeutic targets, here, we interrogated a range of RTT transcriptomic studies spanning different species, models, and MECP2 mutations. A meta-analysis using RNA sequencing data from brains of RTT mouse models, human post-mortem brain tissue, and patient-derived induced pluripotent stem cell (iPSC) neurons was performed using weighted gene correlation network analysis (WGCNA). This study identified a module of genes common to all datasets with the following ten hub genes driving the expression: ATRX, ADCY7, ADCY9, SOD1, CACNA1A, PLCG1, CCT5, RPS9, BDNF, and MECP2. Here, we discuss the potential benefits of these genes as therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders 2.0)

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23 pages, 6537 KiB

Open AccessArticle

Luteolin Treatment Ameliorates Brain Development and Behavioral Performance in a Mouse Model of CDKL5 Deficiency Disorder

by Marianna Tassinari, Nicola Mottolese, Giuseppe Galvani, Domenico Ferrara, Laura Gennaccaro, Manuela Loi, Giorgio Medici, Giulia Candini, Roberto Rimondini, Elisabetta Ciani and Stefania Trazzi

Int. J. Mol. Sci. 2022, 23(15), 8719; https://doi.org/10.3390/ijms23158719 - 5 Aug 2022

Cited by 14 | Viewed by 2471

Abstract

CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene, is characterized by early-onset epilepsy, intellectual disability, and autistic features. Although pharmacotherapy has shown promise in the CDD mouse model, safe and effective clinical treatments are still far off. Recently, we found increased microglial activation in the brain of a mouse model of CDD, the Cdkl5 KO mouse, suggesting that a neuroinflammatory state, known to be involved in brain maturation and neuronal dysfunctions, may contribute to the pathophysiology of CDD. The present study aims to evaluate the possible beneficial effect of treatment with luteolin, a natural flavonoid known to have anti-inflammatory and neuroprotective activities, on brain development and behavior in a heterozygous Cdkl5 (+/−) female mouse, the mouse model of CDD that best resembles the genetic clinical condition. We found that inhibition of neuroinflammation by chronic luteolin treatment ameliorates motor stereotypies, hyperactive profile and memory ability in Cdkl5 +/− mice. Luteolin treatment also increases hippocampal neurogenesis and improves dendritic spine maturation and dendritic arborization of hippocampal and cortical neurons. These findings show that microglia overactivation exerts a harmful action in the Cdkl5 +/− brain, suggesting that treatments aimed at counteracting the neuroinflammatory process should be considered as a promising adjuvant therapy for CDD. Full article

(This article belongs to the Special Issue Molecular Research on Rett Syndrome and Related Disorders 2.0)

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